Current advances in the clinical development of anti-tubercular agents

Tetali, Samanvai Reddy; Kunapaeddi, Eswar; Mailavaram, Raghu Prasad; Singh, Vinayak; Borah, Pobitra; Deb, Pran Kishore; Venugopala, Katharigatta N.; Hourani, Wafa; Tekade, Rakesh K.

doi:10.1016/j.tube.2020.101989

Cited by 32 publications

(18 citation statements)

References 94 publications

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“…isoniazid, rifampicin, pyrazinamide and ethambutol 4 . However, drug-resistant TB (DR-TB) continues to be a potential public health threat due to the critical hindrance with the efficacy of existing drug regimens 5 . In 2019, about 465,000 new incidents of rifampicin-resistant TB (RR-TB), including 78% multidrug-resistant TB (MDR-TB) cases – MTB strain conferring resistance at least to rifampicin and isoniazid were reported, with an estimated 182,000 deaths 3 .…”

Section: Introductionmentioning

confidence: 99%

In vitro anti-TB properties, in silico target validation, molecular docking and dynamics studies of substituted 1,2,4-oxadiazole analogues against Mycobacterium tuberculosis

Deb

Al-Shar’i

Venugopala

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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The alarming increase in multi- and extensively drug-resistant (MDR and XDR) strains of Mycobacterium tuberculosis (MTB) has triggered the scientific community to search for novel, effective, and safer therapeutics. To this end, a series of 3,5-disubstituted-1,2,4-oxadiazole derivatives ( 3a–3i ) were tested against H37Rv, MDR and XDR strains of MTB. Of which, compound 3a with para-trifluorophenyl substituted oxadiazole showed excellent activity against the susceptible H37Rv and MDR-MTB strain with a MIC values of 8 and 16 µg/ml, respectively. To understand the mechanism of action of these compounds ( 3a–3i ) and identify their putative drug target, molecular docking and dynamics studies were employed against a panel of 20 mycobacterial enzymes reported to be essential for mycobacterial growth and survival. These computational studies revealed polyketide synthase (Pks13) enzyme as the putative target. Moreover, in silico ADMET predictions showed satisfactory properties for these compounds, collectively, making them, particularly compound 3a , promising leads worthy of further optimisation.

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Section: Introductionmentioning

confidence: 99%

In vitro anti-TB properties, in silico target validation, molecular docking and dynamics studies of substituted 1,2,4-oxadiazole analogues against Mycobacterium tuberculosis

Deb

Al-Shar’i

Venugopala

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…In comparison, in combination with bedaquiline, SQ109 improved EBA four- to eightfold [ 63 ]. In a multi-arm study, the median time to sputum culture conversion did not improve by substituting SQ109 for ethambutol in standard therapy with rifampin, isoniazid, and pyrazinamide, and this arm of the trial was stopped early for lack of efficacy [ 64 , 65 , 66 ]. SQ109 is generally well tolerated, and rates of adverse effects were similar to those seen in the two treatment groups.…”

Section: Mycobacterial Cell Wallmentioning

confidence: 99%

“…Pyrifazimine was derived based on optimization of other potential riminophenazine analogues. Specifically, by ensuring a substituent with a 2-methoxypyridylamino group at the C-2 position of the phenazine, it was found to have improved pharmacokinetic properties with increased antimycobacterial potency compared to clofazimine without evidence of skin discoloration, which is almost ubiquitously encountered with clofazimine [ 66 , 177 – 179 ]. The reduction in lipophilicity is a significant driver in reducing tissue deposition and subsequent pigmentation change [ 179 ].…”

Section: Impaired Energy Metabolism Including Atp Synthesis Cytochrom...mentioning

confidence: 99%

The Struggle to End a Millennia-Long Pandemic: Novel Candidate and Repurposed Drugs for the Treatment of Tuberculosis

Edwards

Field

2022

Drugs

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This article provides an encompassing review of the current pipeline of putative and developed treatments for tuberculosis, including multidrug-resistant strains. The review has organized each compound according to its site of activity. To provide context, mention of drugs within current recommended treatment regimens is made, thereafter followed by discussion on recently developed and upcoming molecules at established and novel targets. The review is designed to provide a clinically applicable understanding of the compounds that are deemed most currently relevant, including those already under clinical study and those that have shown promising pre-clinical results. An extensive review of the efficacy and safety data for key contemporary drugs already incorporated into treatment regimens, such as bedaquiline, pretomanid, and linezolid, is provided. The three levels of the bacterial cell wall (mycolic acid, arabinogalactan, and peptidoglycan layers) are highlighted and important compounds designed to target each layer are delineated. Amongst others, the highly optimistic and potent anti-mycobacterial activity of agents such as BTZ-043, PBTZ 169, and OPC-167832 are emphasized. The evolving spectrum of oxazolidinones, such as sutezolid, delpazolid, and TBI-223, all aiming to exceed the efficacy achieved with linezolid yet offer a safer alternative to the potential toxicity, are reviewed. New and exciting prospective agents with novel mechanisms of impact against TB, including 3-aminomethyl benzoxaboroles and telacebec, are underscored. We describe new diaryloquinolines in development, striving to build on the immense success of bedaquiline. Finally, we discuss some of these compounds that have shown encouraging additive or synergistic benefit when used in combination, providing some promise for the future in treating this ancient scourge.

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“…It is a communicable disease caused by the bacterium Mycobacterium tuberculosis (MTB) that primarily affects the lungs, resulting in pulmonary TB [ 2 ]. TB can also infect other sites of the body, causing extrapulmonary TB [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Antitubercular, Cytotoxicity, and Computational Target Validation of Dihydroquinazolinone Derivatives

et al. 2022

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A series of 2,3-dihydroquinazolin-4(1H)-one derivatives (3a–3m) was screened for in vitro whole-cell antitubercular activity against the tubercular strain H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Compounds 3l and 3m with di-substituted aryl moiety (halogens) attached to the 2-position of the scaffold showed a minimum inhibitory concentration (MIC) of 2 µg/mL against the MTB strain H37Rv. Compound 3k with an imidazole ring at the 2-position of the dihydroquinazolin-4(1H)-one also showed significant inhibitory action against both the susceptible strain H37Rv and MDR strains with MIC values of 4 and 16 µg/mL, respectively. The computational results revealed the mycobacterial pyridoxal-5′-phosphate (PLP)-dependent aminotransferase (BioA) enzyme as the potential target for the tested compounds. In vitro, ADMET calculations and cytotoxicity studies against the normal human dermal fibroblast cells indicated the safety and tolerability of the test compounds 3k–3m. Thus, compounds 3k–3m warrant further optimization to develop novel BioA inhibitors for the treatment of drug-sensitive H37Rv and drug-resistant MTB.

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Current advances in the clinical development of anti-tubercular agents

Cited by 32 publications

References 94 publications

In vitro anti-TB properties, in silico target validation, molecular docking and dynamics studies of substituted 1,2,4-oxadiazole analogues against Mycobacterium tuberculosis

In vitro anti-TB properties, in silico target validation, molecular docking and dynamics studies of substituted 1,2,4-oxadiazole analogues against Mycobacterium tuberculosis

The Struggle to End a Millennia-Long Pandemic: Novel Candidate and Repurposed Drugs for the Treatment of Tuberculosis

Antitubercular, Cytotoxicity, and Computational Target Validation of Dihydroquinazolinone Derivatives

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